ABSTRACT
AIMS: In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial. METHODS AND RESULTS: MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. CONCLUSIONS: The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).
ABSTRACT
Thalidomide has indications for the treatment of several immune-related, neoplastic, and inflammatory diseases, in both adults and children. Despite numerous therapeutic indications for the application of thalidomide, the influence of that drug upon skeletal system has not been recognized. The aim of the present study was to investigate the effects of thalidomide on the osseous tissue in young rats. The experiments were carried out on 5-week-old male Wistar rats. The animals were administered thalidomide in the doses of 15, 30 or 60 mg/kg p.o. over the period of 1, 3 or 6 weeks. The body mass gain, bone mass in the tibia, femur and L-4 vertebra, histomorphometric parameters of the femur (width of trabeculae, width of epiphyseal cartilage, the transverse cross-sectional area of the bone marrow cavity and the cortical bone) and the tibia (width of osteoid, diaphysis transverse growth, the transverse cross-sectional area of the bone marrow cavity and the cortical bone) were studied. The investigations carried out provide, for the first time, information concerning the influence of thalidomide upon bone remodeling processes in young rats. The effects of thalidomide on the skeletal system of young rats depended on the dose and upon application time. After administration of doses 15, 30 and 60 mg/kg p.o. for 1 and 3 weeks, no influence of thalidomide was noted upon the examined macrometric parameters and histomorphometric parameters of femur, tibia and L-4 vertebra in young rats. Significant disturbances of bone remodeling in young rats have been observed after 6 weeks of thalidomide application, while the progression of those changes increased with the increase of the dose administered. After administering the dose of 15 mg/kg p.o. for the period of 6 weeks, no significant changes were found, as regards the macrometric and histomorphometric parameters of bones. Thalidomide, applied 6 weeks in the dose of 30 mg/kg p.o., and in particular in the dose of 60 mg/kg p.o., turned out to disturb bone remodeling processes. In animals administered thalidomide in the dose of 60 mg/kg p.o., reduction mass of tibia, femur, and L-4 vertebra has been observed. In compact bone, thalidomide reduced the diaphysis transverse growth of tibia, reduced the width of osteoid, as well as reduced the transverse cross-sectional area of cortical bone, increased the transverse cross-sectional area of marrow cavity, and increased the transverse cross-sectional area of the marrow cavity/transverse cross-sectional area of the diaphysis ratio of tibia and femur. In cancellous bone, thalidomide reduced the width of bone trabeculae, and increased the width of epiphyseal cartilage. On the basis of the results obtained, one can conclude that thalidomide applied for 6 weeks in the dose of 60 mg/kg p.o. inhibited the bone formation processes and increased the bone resorption in young rats.
